Slide 1

Mr Chairman, Ladies and Gentlemen, thank you very much for having me here. It’s a real pleasure to be here in the EDTA conference. I’d like to thank the organising committee for inviting me here. One of the very few American originating speakers. I also would like to thank the audience for being here today, for one it is the very last day of this whole symposium and the meeting. Usually, in the United States on the very last day, the very last symposium is like a ghost town there’s no one around. Then the other thing is these are probably the survivors of last night because I wasn’t sure whether I was in Barcelona or Baghdad for the explosives going around. So, the group here probably survived the whole thing, you can still hear the explosives so it will be an exciting talk over the next 15 or 20 minutes. What I’m going to do is as Doctor Fiaccadori explained, he gave an excellent talk and laid out the whole process, I’d like to talk about insulin resistance in the critically ill patients with a specific emphasis on the acute kidney injury patients and how it implements or how it sort of implicates the whole process of outcomes and therapy.

Slide 2

As a way of introduction, I have to show you a couple of slides in terms of the acute renal failure itself. This is a slide that’s taken from a very recent article from Xue colleagues showing the dialysis related mortality or the patients that are dieing with their own dialysis modality while they have acute kidney injury in the hospital. As you can see, clearly there’s a huge mortality rate about 35-40% of these hospitalised patients who have been exposed to a dialytic modality, if they have acute kidney injury indicating that this is a very important process.

Slide 3

We also know that there are multiple reasons why these patients are exposed to this high mortality or at high risk of mortality and one of them is the nutritional state of these patients and I’m not going to go into too much detail and again by the elegant talk given by Doctor Fiaccadori sort of exemplifies this is an important process in addition to multiple other things that are going on in these patient populations.

Slide 4

Of course, when we talk about nutritional state, one can also clearly understand that or think that there are a lot of problems and not only one that’s leading to this very complex dysmetabolic and nutritional abnormality that we observe in these patients. This is a very limited rather simple slide sort of listing all these processes that are associated with increased catabolism or decreased anabolism in the patients with acute kidney injury or in the critically ill condition in the ICU setting. Again, it would be naïve to think that there’s only one thing that’s really important but there are a lot of things that are really putting these patients at high risk and because of the time limitations and the extensive list of things, I’m just going to focus on a couple of things especially in the insulin resistance process.

Slide 5

Now when I do that I usually show this slide. This has been shown by Doctor Fiaccadori as well. I think one thinks about the nutritional aspects for a long period of time just giving nutrition to the patients but we also need to understand that nutrition and metabolism go hand in hand and one cannot sort of think that a nutritional modality is going to work without really thinking about its metabolic implications. With that in mind we have come up with this concept of this acute renal failure initiation or the progression of this acute kidney injury or the critical illness is closely related to several well known metabolic derangements. At the beginning of this whole process it is pretty well known that the cytokine driven inflammation plays a significant role in acute kidney injury and again especially in the patients with chronic illness or acute illness in the critically ill setting. Now, once you have this cytokine driven inflammation that may subsequently lead to other metabolic problems such as oxidative stress, insulin resistance and some other metabolic pathways that I don’t have time to go into too much detail. At the end of this half of these metabolic things sort of pan out. You either lead to a resolution recovery or actually you have this acute kidney injury maintained for a period of time, some of the patients dieing and again, if you have a critically ill condition that is a patient on dialysis usually the mortality rate is about 30-40% at least in the United States.

Slide 6

Now, what I’m going to show you today over the next 10 minutes or so is some data that have been accumulated from our PICARD network which stands for the Project to Improve Acute Renal Disease in the ICU setting. This is a study of a prospective observational cohort of 648 acute kidney injury patients at 5 United States centres and the data collected is between 1999-2001. I’m showing this information over here just to give you the disclaimer that this is sort of an old database. Things might have changed over the time and I do accept that fact but unfortunately, this is all the data that we have at this point. I can tell you this is probably the biggest if not the only biggest dialysis cohort or the AKI cohort that we have in our hands in terms of acute kidney injury.

Slide 7

The data again, related to insulin resistance or the glucose metabolism is going to be a subset analysis of the 648 patients, 618 patients actually of the data that is completely available. It’s a total of 90 patients and the demographics of the patients are listed here and I’m not going to go into too much detail again because of time sake but it is a reflection of what we had over the 600 patients as well.

Slide 8

We were interested in a number of metabolic and nutritional outcomes some of the nutritional outcomes are reported somewhere else but the metabolic outcomes that we were interested in are listed here especially the insulin and the insulin growth factor 1 pathway, cytokines, daily glucose and in addition to that we also measured some oxidative stress markers which are not going to be shown here today.

Slide 9

Again, let me start with the specific area that we’re interested in which is the insulin resistance. Why do we think insulin resistance is an important issue? I have to say for people who are interested in this specific area it has been long known that insulin resistance or the hyperglycaemia of critical illnesses is an important issue for these patients.

Slide 10

We already knew many years ago that the patients who were in the ICU have high glucose levels but it wasn’t until the landmark Van den Berghe study that nobody really paid that much attention to. In this study and again I’m not going to go into too much detail it was shown that if you put patients in the ICU setting and an intensive therapy of insulin versus a conventional therapy and again the biggest difference is you can see the average glucose is 103 versus 153, you seem to have a significant impact in the outcomes.

Slide 11

This initial study was published in 2001 and here on this left side of this slide you can see the ICU outcomes in the intensive treatment versus conventional. There’s about a 4% difference in the overall mortality and then in-hospital mortality is about the same difference.

Slide 12

Now if you really read the lines of this initial paper that was published in 2001, there’s also one other information that is very important and relevant to this audience which is the fact that in the patients who were on the conventional therapy versus the intensive therapy the risk of developing acute kidney injury was also significantly different. In the conventional therapy it was 7.6% versus a 4.5% indicating that this insulin therapy might also have some impact in the acute kidney injury as well.

Slide 13

Again, the biggest question is when you have such impressive information and insulin being so important what is the mechanism that’s leading to this specific problem? I show this slide just to show you people that insulin signalling and the insulin pathways are extremely complicated. This is a slide that I took from a 2003 publication that was published in Science. I don’t know any of the terms, actually more than 90% of the terms other than the insulin over here and the only things that really make sense to me are these JNK, STAT and BAD. The only terms that I’m really familiar with. All the rest are all these complicated terms that are listed here and again, just the fact that this is a very complicated process and one cannot easily figure out what’s happening in these patients.

Slide 14

If you go back to uraemia itself, we already knew many years ago from this study by Doctor Mitch and colleagues that glucose utilisation in uraemia is altered such that if you take a group of rats and expose them to acute renal failure and compare them to sham operated rats and you look at their level of response in terms of protein synthesis, the insulin therapy, you see that the acute renal fats do not seem to have that much of a protein synthesis as compared to the sham operated rats, indicating that the uraemia itself sort of alters the glucose utilisation in these patients or in these animals.

Slide 15

Slide 16

Slide 17

With that in mind we went back to our sub cohort of 90 patients in the PICARD data and we initially measured the insulin concentrations in these patients. Once we measured the 90 patients with their insulin concentrations, we divided them into survivors versus non-survivors and as you can see, in this cohort of patients with acute kidney injury in the critically ill setting the insulin levels were significantly different in the survivors versus the non-survivors such that the non-survivors had significantly higher levels up to the levels of 60 μunits /ml indicating that it’s a substantially increased insulin concentration.

Slide 18

If you look at the insulin concentration in terms of predicted mortality, you can see that as the insulin concentration went up in these patients there is a higher risk of dieing. The odds ratio was about 2 and a half times more likely in these patients with the highest insulin compared to the ones that were in the lowest quartile. Again, an important fact that needs to be mentioned here even if you look at the patients that are in the lowest quartile the median of this, the mean of this quartile was about 9.3 almost twice as much of the normal that you would see in a patient population with no acute kidney injury.

Slide 19

We subsequently went back and looked at the glucose concentrations of the same patients and see if there is any difference in terms of the glucose. As you can see, this slide was shown in the previous talk and as the glucose concentrations went up in the highest quartile over here there was over a 70% increased risk of odds ratio of death in these patients with the highest quartile as compared to the lowest quartile over here. Again indicating that the higher the glucose, the more likely the patient is going to die.

Slide 20

Again this is a subgroup of 90 patients with acute kidney injury so we’re really looking at the ones that have an acute kidney injury in the ICU setting and if you go back and look at the glucose levels on a daily basis over a period of 4-5 weeks, again splitting the patients into non-survivors versus the survivors, the non-survivor patients that started with a high glucose concentration and continued to have a high glucose concentration throughout the 5 weeks of ICU stay versus the ones who survived the whole process but have a lower glucose concentration, again indicating that the glucose concentration is an indicator of poor outcomes the higher the glucose, the worse the patients do.

Slide 21

Again going back to this concept why would it be the case? First one thing that you may be looking at some diabetic patients and that might be the risk profile that’s explaining these poor outcomes. If you look at the diabetics versus non-diabetics in these 90 patients, there were literally no differences between insulin IGF,  IGF-1 binding protein and binding protein 3 in these patients indicating that this diabetes itself was not the reason why these patients were at high risk. Another reason that might be interesting in this complicated process of endothelial dysfunction.

Slide 22

This is the data that was published by Doctor Van den Berghe as a post hoc analysis looking at the ADMA concentrations of the patients who have been on intensive therapy here and the black dots over here the filled dots versus the conventional therapy and as you can see, the ADMA levels are substantially and significantly lower in the intensive therapy versus the conventional therapy over here. I’m not going to go into too much detail about this but the next speaker is going to give you information about the ADMA itself.

Slide 23

Another possible pathway that might be the insulin growth factor 1, IGF1 pathway that is closely associated with this whole process of insulin sensitivity.

Slide 24

And with that in mind we also went back and looked at IGF and IGF binding protein axis. Here’s the data for IGF-1 and IGF binding protein 1 and as you can see, the survivors had a higher IGF-1 and a lower IGF-1 binding protein compared to the non-survivors. The lower IGF-1 here and the higher IGF-1 binding protein 1.

Slide 25

If you look at IGF binding protein 3 which the highest the better for the patients that has been shown in many other studies the survivors had a higher concentration as compared to the non-survivors with a P approaching 0.2. So with that whole process taken together one could clearly indicate that insulin resistance is an important issue.

Slide 26

One piece of evidence that also supports the fact that insulin resistance might be an important process that needs to be targeted as a therapy is this intriguing study by Gore and colleagues a surgical group from the University of Texas Medical Branch in Galvestion. What they have done is they took a total of 5, actually a total of 10 burned patients without necessarily having acute kidney injury but just critically ill and put those patients into placebo versus metformin to improve their glucose concentrations and the study was simply looking at the fractional synthetic rate of protein synthesis and as you can see, this is the placebo group over here these patients over a 5-day period of placebo improved their protein synthesis to some extent but for the patients who were treated in terms of metformin a hyperglycaemic agent you can see that the effect was more pronounced in these patients who were receiving this therapy indicating that if one actually targets the hyperglycaemia of critical illness, one might have a positive impact on the functional synthetic rate of protein synthesis and that might be a mechanism where you can improve the nutritional status of the patients.

Slide 27

So as a summary, I can tell you that certain metabolic derangements such as insulin resistance and I didn’t show you the slides in terms of oxidative stress these are downstream effectors of dysregulated inflammation. They subsequently follow the excessive inflammatory response in acute kidney injury. I can clearly tell you that these are acute kidney injury specific. These are targets for patients that have acute kidney injury in the ICU and they provide an attractive target for the improvement of the overall morbidity and mortality in these patients. Thank you very much.

Slide 28

Chairman: Thank you Doctor Ikizler questions?

Question: Do you think that the monitoring of glycosylated haemoglobin may add a value to the monitoring of glucose levels?

Dr. Ikizler: Insulin did you say’

Question: No glycosylated haemoglobin.

Dr. Ikizler: Glycosylated haemoglobin. You know I’ve never thought about that. It might be but I really didn’t think about that in these patients. I think what we need to do is first initially start looking at the glucose in a much tighter fashion and try to control. As a link to the previous speaker over here I think this issue was raised. Any nutritional intervention that’s going to create more insulin resistance is not a fine thing or a good thing in these patients. The best example is the effect of an anabolic growth hormone which is shown to have a bad impact because it induces insulin resistance in the patients.

Question: Ok, as long as insulin resistance has a good impact on survival of the patients with acute renal failure. Are there any studies that showed or have demonstrated a role for the glitazones in this context or not?

Dr. Ikizler: Again the only study that I can tell you in terms of targeting glucose control is the insulin therapy versus and the very small study by the metformin. But nobody has used the TCDs in this patient population. Clearly it’s a very interesting and intriguing intervention to do in these patients. Since you’re going to be giving it for a short period of time you shouldn’t have any side effects in terms of long-term complications and it shouldn’t induce a hyperglycaemia. So it is a very intriguing intervention. But I don’t know of any studies that have looked at that.

Question: What do you think about the risk of metformin of inducing acidosis in this kind of patients?

Dr. Ikizler: Again that study I made the disclaimer that this was not acute kidney injury patients. Yes it is a possibility, so I don’t really propose that metformin should be used but that study was shown to prove the concept that if you improve hyperglycaemia, you may actually have a positive impact on the protein synthesis and the overall protein metabolism in these patients. I think you are appropriately pointing out that that’s not the appropriate medicine. TCDs is much more of a better target, if you cannot do it with the insulin therapy.

Chairman: Any other questions? Yes we have a question from the rear of the room.

Question: I would like to ask you how do you think that metformin which is supposed to do no more than decrease glucose output from the liver, does it increase the protein synthesis your insulin levels, insulin of course is anabolic but insulin levels would rather fall than increase on metformin?

Dr. Ikizler: That’s an excellent question in terms of trying to understand the mechanism. I think the process over there is to prove the concept that it is the hyperglycaemia that’s having a bad effect. So the issue of whether it’s hyperglycaemia or more insulin making a positive effect has not been clarified by the Van den Berghe studies. It could be either way. In that study metformin clearly decreases the glucose levels and just by simply decreasing hyperglycaemia you have a positive impact. Why that happens is a very complex process. It is possible that just having too much glucose around has an impact on the insulin signalling as well. That might be another mechanism why you have insulin resistance in these patients. But purely thinking that study only proves the fact that hyperglycaemia, if treated is a player in terms of the protein catabolism in these patients.

Chairman: Ok if there are no other questions thank you very much Doctor Ikizler.